Novel naphthoquinone-1H-1,2,3-triazole hybrids: Design, synthesis and evaluation as inductors of ROS-mediated apoptosis in the MCF-7 cells.

The search for novel anticancer drugs is essential to expand treatment options, overcome drug resistance, reduce toxicity, promote innovation, and tackle the economic impact. The importance of these studies lies in their contribution to advancing cancer research and enhancing patient outcomes in the battle against cancer. Here, we developed new asymmetric hybrids containing two different naphthoquinones linked by a 1,2,3-1H-triazole nucleus, which are potential new drugs for cancer treatment. The antitumor activity of the novel compounds was tested using the breast cancer cell lines MCF-7 and MDA-MB-231, using the non-cancer cell line MCF10A as control. Our results showed that two out of twenty-two substances tested presented potential antitumor activity against the breast cancer cell lines. These potential drugs, named here 12g and 12h were effective in reducing cell viability and promoting cell death of the tumor cell lines, exhibiting minimal effects on the control cell line. The mechanism of action of the novel drugs was assessed revealing that both drugs increased reactive oxygen species production with consequent activation of the AMPK pathway. Therefore, we concluded that 12g and 12h are novel AMPK activators presenting selective antitumor effects.

Grandchildren's Longevity and Their Grandfathers' POW Trauma in the U.S. Civil War.

I document the transmission of a grandfather's net nutritional deprivation and psychosocial stress in young adulthood across multiple generations using the grandfather's ex-prisoner of war (ex-POW) status in the U.S. Civil War (1861-1865). Using a newly created dataset, I uncover an association between a grandfather's ex-POW status and the longevity after age 45 of his sons and male-line grandsons but not of his daughters, granddaughters, female-line grandsons, children-in-law, or grandchildren-in-law. Male-line grandsons lost roughly a year of life at age 45 (4% of remaining life expectancy) if descended from ex-POWs who suffered severe captivity conditions than if descended from non-POWs. If their grandfathers faced a less harsh captivity, male-line grandsons lost less than a year of life compared with those descended from non-POWs. I find that the grandfather's age at exposure and the grandson's education, as well as the son's and the grandson's poor late gestational conditions (proxied by season of birth), mediate this relationship. I rule out socioeconomic status, marriage and mortality selection, and cultural or psychological transmission from grandfathers to grandsons as explanations. I cannot rule out an epigenetic explanation.

A Supramolecular Injectable Methacryloyl Chitosan-Tricine-Based Hydrogel with 3D Printing Potential for Tissue Engineering Applications.

Printable hydrogels have attracted significant attention as versatile, tunable, and spatiotemporally controlled biomaterials for tissue engineering (TE) applications. Several chitosan-based systems are reported presenting low or no solubility in aqueous solutions at physiological pH. Herein, a novel neutrally charged, biomimetic, injectable, and cytocompatible dual-crosslinked (DC) hydrogel system based on a double functionalized chitosan (CHT) with methacryloyl and tricine moieties (CHTMA-Tricine), completely processable at physiological pH, with promising three-dimensional (3D) printing potential is presented. Tricine, an amino acid typically used in biomedicine, is capable of establishing supramolecular interactions (H-bonds) and is never explored as a hydrogel component for TE. CHTMA-Tricine hydrogels demonstrate significantly greater toughness (ranging from 656.5 ± 82.2 to 1067.5 ± 121.5 kJ m-3 ) compared to CHTMA hydrogels (ranging from 382.4 ± 44.1 to 680.8 ± 104.5 kJ m-3 ), highlighting the contribution of the supramolecular interactions for the overall reinforced 3D structure provided by tricine moieties. Cytocompatibility studies reveal that MC3T3-E1 pre-osteoblasts cells remain viable for 6 days when encapsulated in CHTMA-Tricine constructs, with semi-quantitative analysis showing ≈80% cell viability. This system's interesting viscoelastic properties allow the fabrication of multiple structures, which couple with a straightforward approach, will open doors for the design of advanced chitosan-based biomaterials through 3D bioprinting for TE.

Bioactive Self-Regulated Liquified Microcompartments to Bioengineer Bone-Like Microtissues.

Designing a microenvironment that drives autonomous stromal cell differentiation toward osteogenesis while recapitulating the complexity of bone tissue remains challenging. In the current study, bone-like microtissues are created using electrohydrodynamic atomization to form two distinct liquefied microcapsules (mCAPs): i) hydroxypyridinone (HOPO)-modified gelatin (GH mCAPs, 7.5% w/v), and ii) HOPO-modified gelatin and dopamine-modified gelatin (GH+GD mCAPs, 7.5%+1.5% w/v). The ability of HOPO to coordinate with iron ions at physiological pH allows the formation of a semipermeable micro-hydrogel shell. In turn, the dopamine affinity for calcium ions sets a bioactive milieu for bone-like microtissues. After 21 days post encapsulation, GH and GH+GD mCAPs potentiate autonomous osteogenic differentiation of mesenchymal stem cells accompanied by collagen type-I gene upregulation, increased alkaline phosphatase (ALP) expression, and formation of mineralized extracellular matrix. However, the GH+GD mCAPs show higher levels of osteogenic markers starting on day 14, translating into a more advanced and organized mineralized matrix. The GH+GD system also shows upregulation of the receptor activator of nuclear factor kappa-B ligand (RANK-L) gene, enabling the autonomous osteoclastic differentiation of monocytes. These catechol-based mCAPs offer a promising approach to designing multifunctional and autonomous bone-like microtissues to study in vitro bone-related processes at the cell-tissue interface, angiogenesis, and osteoclastogenesis.

Overweight grandsons and grandfathers' starvation exposure.

Much of the increase in the prevalence of overweight and obesity has been in developing countries with a history of famines and malnutrition. This paper is the first to examine overweight among adult grandsons of grandfathers exposed to starvation during developmental ages. I study grandsons born to grandfathers who served in the Union Army during the US Civil War (1861-5) where some grandfathers experienced severe net malnutrition because they suffered a harsh POW experience. I find that male-line but not female-line grandsons of grandfathers who survived a severe captivity during their growing years faced a 21% increase in mean overweight and a 2% increase in mean BMI compared to grandsons of non-POWs. Male-line grandsons descended from grandfathers who experienced a harsh captivity faced a 22%-28% greater risk of dying every year after age 45 relative to grandsons descended from non-POWs, with overweight accounting for 9%-14% of the excess risk.

Biomimetic Adhesive Micropatterned Hydrogel Patches for Drug Release.

The optimized physical adhesion between bees' leg hairs and pollen grains-whereby the latter's diameter aligns with the spacing between the hairs-has previously inspired the development of a biomimetic drug dressing. Combining this optimized process with the improved natural mussels' adhesion in wet environments in a dual biomimetic process, it is herein proposed the fabrication of a natural-derived micropatterned hydrogel patch of methacrylated laminarin (LAM-MET), with enriched drug content and improved adhesiveness, suitable for applications like wound healing. Enhanced adhesion is accomplished by modifying LAM-MET with hydroxypyridinone groups, following the patch microfabrication by soft lithography and UV/vis-irradiation, resulting in a membrane with micropillars with a high aspect ratio. Following the biomimetics rational, a drug patch is engineered by combining the microfabricated dressing with drug particles milled to fit the spaces between pillars. Controlled drug release is achieved, together with inherent antibacterial activity against Escherichia coli and Pseudomonas aeruginosa, and enhanced biocompatibility using the bare micropatterned patches. This new class of biomimetic dressings overcomes the challenges of current patches, like poor mechanical properties and biocompatibility, limited adhesiveness and drug dosage, and lack of prolonged antimicrobial activity, opening new insights for the development of high drug-loaded dressings with improved patient compliance.

Bioinspired Oxidation-Resistant Catechol-like Sliding Ring Polyrotaxane Hydrogels.

Adaptable hydrogels have been used in the biomedical field to address several pathologies, especially those regarding tissue defects. Here, we describe unprecedented catechol-like functionalized polyrotaxane (PR) polymers able to form hydrogels. PR were functionalized with the incorporation of hydroxypyridinone (HOPO) moieties into the polymer backbone, with a degree of substitution from 4 to 22%, depending on the PR type. The hydrogels form through the functionalized supramolecular systems when in contact with a Fe(III) solution. Despite the hydrogel formation being at physiological pH (7.4), the HOPO derivatives are extremely resistant to oxidation, unlike common catechols; consequently, they prevent the formation of quinones, which can lead to irreversible bounds within the matrix. The resulting hydrogels demonstrated properties lead to unique hydrogels with improved mechanical behavior obtained by metallic coordination crosslinking, due to the synergies of the sliding-ring PR and the non-covalent (reversible) catechol analogues. Following this strategy, we successfully developed innovative, cytocompatible, oxidative-resistant, and reversible crosslinked hydrogels, with the potential of being used as structural self-materials for a variety of applications, including in the biomedical field.

Children and Grandchildren of Union Army Veterans: New Data Collections to Study the Persistence of Longevity and Socioeconomic Status Across Generations.

This paper introduces four new intergenerational and multigenerational datasets which follow both sons and daughters and which can be used to study the persistence of longevity, socioeconomic status, family structure, and geographic mobility across generations. The data follow the children of Black and White Union Army (US Civil War, 1861-5) veterans from birth to death, linking them to the available censuses. The White samples include an over-sample of children of ex-POWs. A separate collection links grandchildren of White Union Army veterans to their death records. The data were created with high quality manual linkage procedures utilizing a wide variety of records to establish links.

Universal Strategy for Designing Shape Memory Hydrogels.

Smart polymeric biomaterials have been the focus of many recent biomedical studies, especially those with adaptability to defects and potential to be implanted in the human body. Herein we report a versatile and straightforward method to convert non-thermoresponsive hydrogels into thermoresponsive systems with shape memory ability. As a proof of concept, a thermoresponsive polyurethane mesh was embedded within a methacrylated chitosan (CHTMA), gelatin (GELMA), laminarin (LAMMA) or hyaluronic acid (HAMA) hydrogel network, which afforded hydrogel composites with shape memory ability. With this system, we achieved good to excellent shape fixity ratios (50-90%) and excellent shape recovery ratios (∼100%, almost instantaneously) at body temperature (37 °C). Cytocompatibility tests demonstrated good viability either with cells on top or encapsulated during all shape memory processes. This straightforward approach opens a broad range of possibilities to convey shape memory properties to virtually any synthetic or natural-based hydrogel for several biological and nonbiological applications.

Menadione: a platform and a target to valuable compounds synthesis.

Naphthoquinones are important natural or synthetic compounds belonging to the general class of quinones. Many compounds in this class have become drugs that are on the pharmaceutical market for the treatment of various diseases. A special naphthoquinone derivative is menadione, a synthetic naphthoquinone belonging to the vitamin K group. This compound can be synthesized by different methods and it has a broad range of biological and synthetic applications, which will be highlighted in this review.

Design of Protein-Based Liquefied Cell-Laden Capsules with Bioinspired Adhesion for Tissue Engineering.

Platforms with liquid cores are extensively explored as cell delivery vehicles for cell-based therapies and tissue engineering. However, the recurrence of synthetic materials can impair its translation into the clinic. Inspired by the adhesive proteins secreted by mussels, liquefied capsule is developed using gelatin modified with hydroxypyridinones (Gel-HOPO), a catechol analogue with oxidant-resistant properties. The protein-based liquefied macrocapsule permitted the compartmentalization of living cells by an approachable and non-time-consuming methodology resorting to i) superhydrophobic surfaces as a processing platform of hydrogel beads, ii) gelation of gelatin at temperatures < 25 °C, iii) iron coordination of the hydroxypyridinone (HOPO) moieties at physiological pH, and iv) core liquefaction at 37 °C. With the design of a proteolytically degradable shell, the possibility of encapsulating human adipose-derived mesenchymal stem cells (hASC) with and without the presence of polycaprolactone microparticles (µPCL) is evaluated. Showing prevalence toward adhesion to the inner shell wall, hASC formed a monolayer evidencing the biocompatibility and adequate mechanical properties of these platforms for proliferation, diminishing the need for µPCL as a supporting substrate. This new protein-based liquefied platform can provide biofactories devices of both fundamental and practical importance for tissue engineering and regenerative medicine or in other biotechnology fields.

Biological Evaluation of Selected 1,2,3-triazole Derivatives as Antibacterial and Antibiofilm Agents.

BACKGROUND: Resistance to antimicrobial agents is a major public health problem, being Staphylococcus aureus prevalent in infections in hospital and community environments and, admittedly, related to biofilm formation in biotic and abiotic surfaces. Biofilms form a complex and structured community of microorganisms surrounded by an extracellular matrix adhering to each other and to a surface that gives them even more protection from and resistance against the action of antimicrobial agents, as well as against host defenses. METHODS: Aiming to control and solve these problems, our study sought to evaluate the action of 1,2,3- triazoles against a Staphylococcus aureus isolate in planktonic and in the biofilm form, evaluating the activity of this triazole through Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) tests. We have also performed cytotoxic evaluation and Scanning Electron Microscopy (SEM) of the biofilms under the treatment of the compound. The 1,2,3-triazole DAN 49 showed bacteriostatic and bactericidal activity (MIC and MBC 128 µg/mL). In addition, its presence interfered with the biofilm formation stage (1/2 MIC, p <0.000001) and demonstrated an effect on young preformed biofilm (2 MICs, p <0.05). RESULTS: Scanning Electron Microscopy images showed a reduction in the cell population and the appearance of deformations on the surface of some bacteria in the biofilm under treatment with the compound. CONCLUSION: Therefore, it was possible to conclude the promising anti-biofilm potential of 1,2,3-triazole, demonstrating the importance of the synthesis of new compounds with biological activity.

Wartime health shocks and the postwar socioeconomic status and mortality of union army veterans and their children.

We investigate when and how health shocks reverberate across the life cycle and down to descendants in a manual labor economy by examining the association of war wounds with the socioeconomic status and older age mortality of US Civil War (1861-5) veterans and of their adult children. Younger veterans who had been severely wounded in the war left the farm sector, becoming laborers. Consistent with human capital and job matching models, older severely wounded men were unlikely to switch sectors and their wealth declined by 37-46%. War wounds were correlated with children's socioeconomic and mortality outcomes in ways dependent on sex and paternal age group.

Intergenerational transmission of paternal trauma among US Civil War ex-POWs.

We study whether paternal trauma is transmitted to the children of survivors of Confederate prisoner of war (POW) camps during the US Civil War (1861-1865) to affect their longevity at older ages, the mechanisms behind this transmission, and the reversibility of this transmission. We examine children born after the war who survived to age 45, comparing children whose fathers were non-POW veterans and ex-POWs imprisoned in very different camp conditions. We also compare children born before and after the war within the same family by paternal ex-POW status. The sons of ex-POWs imprisoned when camp conditions were at their worst were 1.11 times more likely to die than the sons of non-POWs and 1.09 times more likely to die than the sons of ex-POWs when camp conditions were better. Paternal ex-POW status had no impact on daughters. Among sons born in the fourth quarter, when maternal in utero nutrition was adequate, there was no impact of paternal ex-POW status. In contrast, among sons born in the second quarter, when maternal nutrition was inadequate, the sons of ex-POWs who experienced severe hardship were 1.2 times more likely to die than the sons of non-POWs and ex-POWs who fared better in captivity. Socioeconomic effects, family structure, father-specific survival traits, and maternal effects, including quality of paternal marriages, cannot explain our findings. While we cannot rule out fully psychological or cultural effects, our findings are most consistent with an epigenetic explanation.

A Novel Triazole Derivative Drug Presenting In Vitro and In Vivo Anticancer Properties.

BACKGROUND: Cancer is a major cause of death worldwide, despite many different drugs available to treat the disease. This high mortality rate is largely due to the complexity of the disease, which results from several genetic and epigenetic changes. Therefore, researchers are constantly searching for novel drugs that can target different and multiple aspects of cancer. EXPERIMENTAL: After a screening, we selected one novel molecule, out of ninety-four triazole derivatives, that strongly affects the viability and proliferation of the human breast cancer cell line MCF-7, with minimal effects on non-cancer cells. The drug, named DAN94, induced a dose-dependent decrease in MCF-7 cells viability, with an IC50 of 3.2 ± 0.2 µM. Additionally, DAN94 interfered with mitochondria metabolism promoting reactive oxygen species production, triggering apoptosis and arresting the cancer cells on G1/G0 phase of cell cycle, inhibiting cell proliferation. These effects are not observed when the drug was tested in the non-cancer cell line MCF10A. Using a mouse model with xenograft tumor implants, the drug preventing tumor growth presented no toxicity for the animal and without altering biochemical markers of hepatic function. RESULTS AND CONCLUSION: The novel drug DAN94 is selective for cancer cells, targeting the mitochondrial metabolism, which culminates in the cancer cell death. In the end, DAN94 has been shown to be a promising drug for controlling breast cancer with minimal undesirable effects.

Synthesis and evaluation of the cytotoxic activity of Furanaphthoquinones tethered to 1H-1,2,3-triazoles in Caco-2, Calu-3, MDA-MB231 cells.

Naphthoquinones and 1,2,3-triazoles are structural pharmacophore that is known to impart several cancer cells. This work shows a synthetic methodology to obtain hybrid molecules involving naphthoquinone and triazol scaffold as multiple ligands. A simple and efficient synthetic route was used to prepare a series of sixteen compounds being eight 2-(1-aryl-1H-1,2,3-triazol-4-yl)-2,3-dihydronaphtho[1,2 b]furan-4,5-diones and eight 2-(1-aryl-1H-1,2,3-triazol-4-yl)-2,3-dihydronaphtho[2,3-b]furan-4,9-diones. These compounds were tested in MDA-MB231, Caco-2 and Calu-3 human cancer cells, and among them 7a was the most selective compound on Caco-2 cells, the most sensitized cell line in this study. In silico study suggest that the blockage of topoisomerase I and IIα may be one of the mechanisms of action responsible for the cytotoxic effect of 7a in Caco-2 cells.

Data set from the Union Army samples to study locational choice and social networks.

We describe the publicly available data created by the NIA funded Early Indicators program project, often referred to as the Union Army data, and the subset of these data used in "Persistent Social Networks: Civil War Veterans Who Fought Together Co-Locate in Later Life" (Costa et al., Forthcoming) [1]. This data subset can be used for reproducibility and extensions and also illustrates how the original complex data derived from archival administrative records can be used.

Persistent Social Networks: Civil War Veterans Who Fought Together Co-Locate in Later Life.

We demonstrate the long reach of early social ties in the location decision of individuals and in their older age mortality risk using data on Union Army veterans of the US Civil War (1861-5). We estimate discrete choice migration models to quantify the trade-offs across locations faced by veterans. Veterans were more likely to move to a neighborhood or county where men from their same war company lived and were more likely to move to such areas than to areas where other veterans were located. Veterans also were less likely to move far from their origin and avoided urban immigrant areas and high mortality risk areas. They also avoided areas that opposed the Civil War. This co-location evidence highlights the existence of persistent social networks. Such social networks had long-term consequences: veterans living close to war-time comrades had a 6% lower probability of dying.

Synthesis and Biological Evaluation of Coumarins Derivatives as Potential Inhibitors of the Production of Pseudomonas aeruginosa Virulence Factor Pyocyanin.

Antimicrobial Resistance (AMR) is a serious problem for the humans since it threatens the effective prevention and treatment of an ever-increasing range of infections caused by bacteria, parasites, viruses and fungi. One way around this problem is to act on the virulence factors, produced by bacteria, which increase their infection effectiveness. In view of these facts, new coumarin derivatives were synthesized and evaluated for their anti-virulence biological activity towards Pseudomonas aeruginosa. The results suggest that coumarin derivatives with a secondary carbon at C-3 position reduces P. aeruginosa growth whereas compounds with one additional substituent have a significant effect over pyocyanin production (10k EC50 7 ± 2 µM; 10l EC50 42 ± 13 µM). Moreover, 10k reduces P. aeruginosa motility and biofilm formation, what is compatible with a quorum sensing related mechanism of action.

Hetero-Diels-Alder reactions of novel 3-triazolyl-nitrosoalkenes as an approach to functionalized 1,2,3-triazoles with antibacterial profile.

The generation and reactivity of 3-triazolyl-nitrosoalkenes are reported for the first time. The study showed that hetero-Diels-Alder reaction of these heterodienes is an interesting synthetic strategy to functionalized 1,2,3-triazoles, including 1,2,3-triazolyl-pyrroles, 1,2,3-triazolyl-dipyrromethanes and 1,2,3-triazolyl-indoles. The evaluation of the antibacterial profile against Gram-positive and Gram-negative strains revealed the new 5,5'-diethyldipyrromethane bearing a side chain incorporating a triazole and oxime moieties. The antibacterial profile detected was within the Clinical and Laboratory Standard Institute (CLSI) range and against important Staphylococcus species including Methicillin-resistant strain (S. aureus ATCC 25923, S. epidermidis ATCC 12228 and S. simulans ATCC 27851 and MRSA). Interestingly, this new 1,2,3-triazole presented hemocompatibility and low in silico toxicity profile similar to antibiotics current in use. It also has an usual antibiofilm activity against MRSA, which reinforced its potential as a new antibacterial prototype.